Abstract 2488: Co-targeting EGFR and IGF-1R to sensitize or overcome induced resistance of head and neck cancer models to radiation

Abstract

Abstract Purpose: Emerging data show crosstalk among receptor tyrosine kinases (RTK), e.g., epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor (IGF-1R). Higher IGF-1R expression was associated with resistance to EGFR inhibitors and ionizing radiation (IR). We investigated the effects of cetuximab (EGFR antibody) and A12 (IGF-1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to IR, escape mechanisms from EGFR blockade leading to radioresistance, and strategies to overcome it. Methods: Three HNSCC models (HN-5, FaDu, and UMSCC-1) expressing different levels of EGFR and IGF-1R were studied. The effects of cetuximab and A12 (from Imclone) on cell viability (MTS assay) and radiosensitivity (clonogenic survival assay) were determined. Various scheduling of drugs were examined. Alterations in target signaling were analyzed by Western blots. Results: Cetuximab inhibited viability of cells (14 to 53%) in a cell type dependent manner. The highest EGFR expressing HN-5 was the most responsive to cetuximab. A12 had no effect on cell viability but elicited a moderate radiosensitization of all three cell lines (enhancement factors, EFs, ranged from 1.11 to 1.67). Cetuximab, given 6 h before till 66 h after IR, significantly enhanced the radiosensitivity of HN-5 (EF, 2.55) and FaDu (EF, 1.46), but no effect on UMSCC-1. A 48 h exposure to cetuximab before IR, however, increased radioresistance of HN-5 and FaDu without affecting UMSCC-1. Continuing with cetuximab for 72 h after IR resulted in a net radiation sensitization in HN-5, partially reversed radioresistance in FaDu, and enhanced the radiosensitivity of UMSCC-1. Western blots revealed that cetuximab (48 h) upregulated IGF-1R in FaDu (2.28 fold) and UMSCC-1 (1.26 fold) but, not in HN-5; however, EGFR was upregulated in HN-5. IGF-1R inhibition had no effect on HN-5, reverted the radiation response partially in FaDu, and increased the net radiosensitivity of UMSCC-1. Compared to EGFR inhibition alone, co-targeting of both pathways did not yield a better effect on HN-5, reverted radiosensitivity to the baseline level in FaDu, but further increased UMSCC-1 radiosensitivity. Conclusion: This study showed that tumors responded to prolonged EGFR inhibition by upregulating other pro-survival RTK signaling, e.g. IGF-1R. In HN-5, EGFR was a main pro-survival signaling as EGFR inhibition yielded consistent sensitization that was not enhanced by IGF-1R blockade. UMSCC-1 seemed to rely on EGFR and IGF-1R signaling as dual inhibition yielded better sensitization than single pathway blockade. In FaDu, IGF-1R could become a major pro-survival signaling as it was associated with increased resistance that was only reverted by co-targeting IGF-1R. Taken together our data suggest that therapeutic benefit would result from combining cetuximab and A12 with IR in some HNSCC. Supported by P0-1 CA-06294 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2488. doi:10.1158/1538-7445.AM2011-2488